Mechanisms of Cadmium Neurotoxicity.

Cadmium is a heavy metal that increasingly contaminates food and drink products. Once ingested, cadmium exerts toxic effects that pose a significant threat to human health. The nervous system is particularly vulnerable to prolonged, low-dose cadmium exposure. This review article provides an overview of cadmium's primary mechanisms of neurotoxicity. Cadmium gains entry into the nervous system via zinc and calcium transporters, altering the homeostasis for these metal ions. Once within the nervous system, cadmium disrupts mitochondrial respiration by decreasing ATP synthesis and increasing the production of reactive oxygen species. Cadmium also impairs normal neurotransmission by increasing neurotransmitter release asynchronicity and disrupting neurotransmitter signaling proteins. Cadmium furthermore impairs the blood-brain barrier and alters the regulation of glycogen metabolism. Together, these mechanisms represent multiple sites of biochemical perturbation that result in cumulative nervous system damage which can increase the risk for neurological and neurodegenerative disorders. Understanding the way by which cadmium exerts its effects is critical for developing effective treatment and prevention strategies against cadmium-induced neurotoxic insult.

Cross-Course Harmonized Assignments in Neuroscience.

Neuroscience is inherently interdisciplinary. This interdisciplinarity can be lost due to the self-contained nature of each course in most undergraduate neuroscience programs, leaving students to draw these cross-course relationships on their own. We sought to address this by using short, creative research assignments on a topic of the student's choice ("Deep Dive" assignments) that provided students with the opportunity to explore common applications across two concurrently run core neuroscience courses housed in different departments. We tested whether unifying the available Deep Dive topics across the two courses improved student outcomes. Specifically, students were asked to select a topic of interest from a shortlist shared in the two courses. Our results show that harmonized, concurrent creative assignments across dissimilar neuroscience courses improved outcomes related to student interest in material, confidence in creative problem solving, content recall for the other course, and applicability to real life. To our surprise, there was no added benefit to be in the same topic for both courses. Instead, the addition of harmonized Deep Dive assignments themselves, even if assigned on different topics across the two courses, drove the outcome improvement.

Developmental pyrethroid exposure causes a neurodevelopmental disorder phenotype in mice.

Neurodevelopmental disorders (NDDs) are a widespread and growing public health challenge, affecting as many as 17% of children in the United States. Recent epidemiological studies have implicated ambient exposure to pyrethroid pesticides during pregnancy in the risk for NDDs in the unborn child. Using a litter-based, independent discovery-replication cohort design, we exposed mouse dams orally during pregnancy and lactation to the Environmental Protection Agency's reference pyrethroid, deltamethrin, at 3 mg/kg, a concentration well below the benchmark dose used for regulatory guidance. The resulting offspring were tested using behavioral and molecular methods targeting behavioral phenotypes relevant to autism and NDD, as well as changes to the striatal dopamine system. Low-dose developmental exposure to the pyrethroid deltamethrin (DPE) decreased pup vocalizations, increased repetitive behaviors, and impaired both fear conditioning and operant conditioning. Compared with control mice, DPE mice had greater total striatal dopamine, dopamine metabolites, and stimulated dopamine release, but no difference in vesicular dopamine capacity or protein markers of dopamine vesicles. Dopamine transporter protein levels were increased in DPE mice, but not temporal dopamine reuptake. Striatal medium spiny neurons showed changes in electrophysiological properties consistent with a compensatory decrease in neuronal excitability. Combined with previous findings, these results implicate DPE as a direct cause of an NDD-relevant behavioral phenotype and striatal dopamine dysfunction in mice and implicate the cytosolic compartment as the location of excess striatal dopamine.

A Semester without Exams: Approaches in a Small and Large Course.

Exams carry pedagogical downsides: they can create stress, decrease intrinsic motivation, and tend to reduce opportunities for creative problem-solving. Exams are also difficult to administer when flexibility is paramount, such as during remote learning, when students have special testing conditions, or during a pandemic when a subset of students are sick or in quarantine. To account for these shortcomings, I designed and instituted two completely exam-free undergraduate Neuroscience and Behavior courses in the Spring of 2021, one a large introductory-level course and the other a small upper-level elective course. In the large introductory-level course, I used several methods including Gradescope and new roles for my Teacher's Assistants to keep the grading load manageable. This exam-free approach was evaluated in four areas: creative thinking, interest in the material, stress level, and academic performance. Evaluation of success in these areas was completed via student feedback and by comparing final projects to final projects from previous semesters. The exam-free approach produced favorable or neutral results in every measured outcome. The framework for an exam-free course described here could be a useful starting point for other instructors who want to eliminate exams.

Vesicular monoamine transporter 2 mediates fear behavior in mice.

A subset of people exposed to a traumatic event develops post-traumatic stress disorder (PTSD), which is associated with dysregulated fear behavior. Genetic variation in SLC18A2, the gene that encodes vesicular monoamine transporter 2 (VMAT2), has been reported to affect risk for the development of PTSD in humans. Here, we use transgenic mice that express either 5% (VMAT2-LO mice) or 200% (VMAT2-HI mice) of wild-type levels of VMAT2 protein. We report that VMAT2-LO mice have reduced VMAT2 protein in the hippocampus and amygdala, impaired monoaminergic vesicular storage capacity in both the striatum and frontal cortex, decreased monoamine metabolite abundance and a greatly reduced capacity to release dopamine upon stimulation. Furthermore, VMAT2-LO mice showed exaggerated cued and contextual fear expression, altered fear habituation, inability to discriminate threat from safety cues, altered startle response compared with wild-type mice and an anxiogenic-like phenotype, but displayed no deficits in social function. By contrast, VMAT2-HI mice exhibited increased VMAT2 protein throughout the brain, higher vesicular storage capacity and greater dopamine release upon stimulation compared with wild-type controls. Behaviorally, VMAT2-HI mice were similar to wild-type mice in most assays, with some evidence of a reduced anxiety-like responses. Together, these data show that presynaptic monoamine function mediates PTSD-like outcomes in our mouse model, and suggest a causal link between reduced VMAT2 expression and fear behavior, consistent with the correlational relationship between VMAT2 genotype and PTSD risk in humans. Targeting this system is a potential strategy for the development of pharmacotherapies for disorders like PTSD.

Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens.

The dopamine D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia, Parkinson's disease, and substance use disorders. However, studies investigating the D3R's precise role in dopamine neurotransmission or how it may be exploited to modulate responses to drugs of abuse have produced contrasting results, in part because most D3R-targeted compounds often also interact with D2 receptors (D2R). To resolve this issue, we set out to systematically characterize and compare the consequences of selective D2R or D3R antagonists on the behavioral-stimulant properties of cocaine in mice, and to identify putative neurobiological mechanisms underlying their behavior-modifying effects. Pretreatment with the selective D2R antagonist L-741,626 attenuated, while pretreatment with the selective D3R antagonist PG01037 enhanced, the locomotor-activating effects of both acute cocaine administration as well as sensitization following repeated cocaine dosing. While both antagonists potentiated cocaine-induced increases in presynaptic dopamine release, we report for the first time that D3R blockade uniquely facilitated dopamine-mediated excitation of D1-expressing medium spiny neurons in the nucleus accumbens. Collectively, our results demonstrate that selective D3R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D2R antagonism or nonselective D2-like receptor antagonists, and is likely mediated by facilitating D1-mediated excitation in the nucleus accumbens. These findings provide novel insights into the neuropharmacological actions of D3R antagonists on mesolimbic dopamine neurotransmission and their potential utility as pharmacotherapeutics.